AN1I8IC1IC USL IN 1nL CkI1ICALL ILL

M|chae| S. N|ederman, M.D.

Cha|rman, Department of Med|c|ne
W|nthrop-Un|vers|ty nosp|ta|
M|neo|a, N

rofessor of Med|c|ne
V|ce-Cha|rman, Department of Med|c|ne
SUN at Stony 8rook
resenter D|sc|osures ke|ated 1o 1h|s
resentanon
Mlchael S. nlederman, M.u.
Commerclal dlsclosures:
Ponorarlum and consulung: 8ayer/nekLar, Sano-
Avenus, zer, Merck, CublsL
non-commerclal dlsclosure: Advlsory board luA,
luSA/A1S PA Culdellne Commluee
8esearch CranL: 8ayer/nekLar, Sano-Avenus, CublsL
Cb[ecnves
Aer Lhls course, you should be able Lo:
Lxplaln mechanlsms of acuon of common anubloucs
use pharmacoklneucs and pharmacodynamlcs Lo
opumlze Lherapy agalnsL drug-reslsLanL organlsms
Apply prlnclples of responslble anublouc use for Lhe
crlucally lll and prlnclples of anumlcroblal
sLewardshlp

4
MLCnANISMS CI AC1ICN
8acLerlcldal: klll bacLerla by lnhlblung cell wall
synLhesls or key meLabollc funcuons
enlcllllns, cephalosporlns, amlnoglycosldes,
uroqulnolones, vancomycln, rlfampln, dapLomycln,
meLronldazole
8acLerlosLauc: lnhlblL growLh , do noL lnLerfere wlLh
cell wall synLhesls, rely on hosL defenses Lo ellmlnaLe
bacLerla, relevanL lf neuLropenlc
Macrolldes, LeLracycllne, sulfa drugs,
chloramphenlcol,llnezolld, cllndamycln
MIC and M8C
MlC: concenLrauon of anublouc LhaL lnhlblLs Lhe
growLh of 90 of a sLandard slzed lnoculum, no
vlslble growLh
M8C: mlnlmum concenLrauon kllllng 99.9 of a
sLandard slzed lnoculm
MlC ls used Lo dene sensluvlLy" of an organlsm Lo
a speclc anublouc, buL conslders only Lhe serum
concenLrauon and nC1 Lhe concenLrauon aL Lhe slLe
of lnfecuon.

In treanng severe VA w|th a
carbapenem, emcacy |s |mproved |f
A. Lhe serum concenLrauon exceeds Lhe MlC for aL
leasL 40 of Lhe doslng lnLerval
8. Lhe area under Lhe concenLrauon ume curve dlvlded
by MlC ls aL leasL 123
C. uoslng ls once dally
u. doslng ls glven by conunuous lnfuslon
L. lL ls never used as monoLherapy

In treanng severe VA w|th a
carbapenem, emcacy |s |mproved |f
A. Lhe serum concenLrauon exceeds Lhe MlC for aL
leasL 40 of Lhe doslng lnLerval
8. Lhe area under Lhe concenLrauon ume curve dlvlded
by MlC ls aL leasL 123
C. uoslng ls once dally
u. doslng ls glven by conunuous lnfuslon
L. lL ls never used as monoLherapy

C
max
(peak)
Time above MIC
Half life
Time
A
n
t
i
b
i
o
t
i
c

s
e
r
u
m

c
o
n
c
e
n
t
r
a
t
i
o
n

MIC
AUC
C
min
(trough)
AUIC
24
=
AUC
24
MIC
18
harmacok|nenc]harmacodynam|c
r|nc|p|es

nAkMACCDNAMIC CCNSIDLkA1ICNS
8acLerlcldal ln a concenLrauon-dependenL fashlon:
amlnoglycosldes, qulnolones, keLolldes, dapLomycln
8acLerlcldal ln a ume-dependenL fashlon (lf > MlC for aL
leasL 40 of Lhe doslng lnLerval) : beLa-lacLams,
carbapenems, azLreonam, macrolldes, llnezolld
1lme-dependenL wlLh prolonged and perslsLenL kllllng:
cllndamycln, vancomycln, azlLhromycln, LeLracycllnes.
(AulC and Lrough may mauer ln addluon Lo ume > MlC)
rolonged AL agalnsL gram-negauves:
amlnoglycosldes, qulnolones, LeLracycllnes, rlfampln
Llule or no AL for gram-negauves: beLa-lacLams
(excepL penems)
No 8eneht Irom ro|onged Infus|on
8efore and aer
comparlson of Lwo ume
perlods wlLh 30 mlnuLe
lnfuslon vs. 3 hour
lnfuslon of plp/Laz,
cefeplme, carbapenem
1reaLmenL success Lhe
same ln boLh groups (36
vs 31). Same morLallLy
Arnold PM eL al. Ann
harmacoLher 2013.

11
%

o
f

p
a
t
i
e
n
t
s

r
e
m
a
i
n
i
n
g

c
u
l
t
u
r
e
-
p
o
s
i
t
i
v
e

Days of treatment
0 2 4 6 8 10 12 14
0
100
75
50
25
AUIC 125-250
AUIC > 250
AUIC < 125
Ciprofloxacin: Eradication vs AUIC
Forrest A, Antimicrobial Agents Chemother 37:1073
1081, 1993.


1he fo||ow|ng annb|oncs penetrate we||
|nto resp|ratory secrenons except
A. LeLracycllne
8. eryLhromycln
C. clprooxacln
u. cllndamycln
L. vancomycln

1he fo||ow|ng annb|oncs penetrate we||
|nto resp|ratory secrenons except
A. LeLracycllne
8. eryLhromycln
C. clprooxacln
u. cllndamycln
L. vancomycln

LNL1kA1ICN
lnlLAMMA1lCn
lnuLLnuLn1 (Lllu
SCLu8LL) CCCu
LnL18A1lCn
Chloramphenlcol
Macrolldes
1eLracycllnes
Culnolones
1rlmeLhoprlm/sulfa
keLolldes
Llnezolld
lnlLAMMA1lCn
uLLnuLn1 (CC8L?
Lllu SCLu8LL) CC8
LnL18A1lCn
enlcllllns
Cephalosporlns
Amlnoglycosldes
Carbapenems
MonbacLams
vancomycln
Iactors Aecnng C||n|ca| Success In
neumon|a 1herapy

L|ppman et a|. Curr Cp|n
Infect D|s 2013, |n press
IAC1CkS AIILC1ING AN1I8IC1IC
CCNCLN1kA1ICNS IN 1nL LUNG
eneLrauon, roLeln 8lndlng, volume of ulsLrlbuuon (vd), Clearance
Cen enhanced renal clearance (beLa-lacLams) ln hyperdynamlc
sepuc pauenLs (A8C, augmenLed renal clearance)
volume of dlsLrlbuuon > 3L means concenLrauon ouLslde of plasma
Llpophlllc drugs have a hlgh vd
Pydrophlllc drugs expand Lhelr vd wlLh sepsls and leaky
caplllarles" (can underdose)
CbeslLy: lf use l8W can underdose (esp llpophlllc drugs).
Cenerally use 18W, 8u1 lf calculaLe dose on 18W can overdose
hydrophlllc drugs (exLracellular waLer does noL expand as much).
lree drug ls acuve and Lhus wlLh low serum proLelns, may lncrease
8C1P vd and Clearance

8L1A-LAC1AMS
All wlLh beLa-lacLam rlng: penlcllllns, cephalosporlns, monobacLams,
carbapenems
lnLerfere wluhe synLhesls of bacLerlal cell wall pepudoglycans by blndlng
Lo 8s
enlcllllns: anu-SLaphylococcal, anu-seudomonal
Can also exLend specLrum by comblnlng wlLh beLa-lacLamase
lnhlblLors
Cephalosporlns: llrsL Lo fourLh generauon wlLh aLrend Lo more gram-
posluve coverage wlLh earller agenLs, more speclallzed wlLh laLer agenLs
Carbapenems (lmlpenem, meropenem, dorlpenem): Lhe broadesL
specLrum agenLs , reslsLance can emerge durlng monoLherapy vs. .
aeruglnosa
MonobacLam (AzLreonam): gram-negauve acuvlLy only, no cross reacuvlLy
Lo Cn allergy

UINCLCNLS
Interfere w|th DNA gyrase and |ead to ce|| |ys|s
Lar||er agents marg|na| vs. gram pos|nves:
ooxac|n, c|prooxac|n
C|prooxac|n |s most acnve aga|nst . aerug|nosa
Levooxac|n 7S0 mg acnve vs. . aerug|nosa
Newer agents w|th enhanced gram -pos|nve acnv|ty
Cra|] or IV agents: Gem|oxac|n (C) >
Mox|oxac|n(C,IV) > Levooxac|n (C,IV)
Mox|oxac|n w|th anaerob|c acnv|ty
Graveyard: 1emaoxac|n, trovaoxac|n, sparoxac|n,
grepaoxac|n, ganoxac|n

u|no|one therapy for pneumococc|
A. ls never assoclaLed wlLh anublouc reslsLance
8. ls more llkely Lo be eecuve wlLh levooxacln Lhan
wlLh moxloxacln
C. ls adequaLe by lLself for lCu admlued CA
u. can have emcacy predlcLed by examlnlng Lhe peak
serum concenLrauon relauve Lo Lhe MlC of Lhe LargeL
organlsm
L. ls equally eecuve for all qulnolones

u|no|one therapy for pneumococc|
A. ls never assoclaLed wlLh anublouc reslsLance
8. ls more llkely Lo be eecuve wlLh levooxacln Lhan
wlLh moxloxacln
C. ls adequaLe by lLself for lCu admlued CA
u. can have emcacy predlcLed by examlnlng Lhe peak
serum concenLrauon relauve Lo Lhe MlC of Lhe LargeL
organlsm
L. ls equally eecuve for all qulnolones

Are u|no|ones 1he 1herapy of Cho|ce for
Leg|one||a ?
6 cllnlcal Lrlals of levooxacln for CA lncluded 73
wlLh Leglonella.
300 mg x 7-14 days, 730 mg x 3 days
93.6 success ln mlld-moderaLe, 91.6 ln severe
?u eL al: ChesL 2004, 123:2133-2139.
ooled daLa from 8 Lrlals of moxloxacln: 4 p.o., 4 lv/
oral
Moxl 400 mg/day for 7-14
Success : 93.2 vs. 79.3 , moxl vs. comparaLors
Carau ! eL al, ! ChemoLher 2010, 22:264-6

Shou|d We NC1 Use u|no|ones Ior A
I|rst ICU Infecnon?
239 lCu pauenLs wlLh no prlor
anublouc exposure
MuluvarlaLe analysls of rlsks for
acqulrlng Mu8 paLhogens
77 pauenLs wlLh lCu
acqulred Mu8 organlsms (30
were lnfecuon)
MuluvarlaLe rlsks for Mu8
acqulsluon: lC use (C8
3.3), durauon anubloucs
(C8 1.1).
Maybe reserve qulnolones for a
second course of lCu lnfecuon
0
5
10
15
20
25
30
35
40
%MDR %MRSA %ESBL
Case
Control
Nse|r et a|. Cr|t Care Med 200S, 33:283
N|ederman. Cr|t Care Med 200S, 33:443.
Lmp|r|c I|uoroqu|no|one 1herapy of
Severe CA |n a 18 Lndem|c Area
77 cases 18 Lo lCu w/l 1 week
of admlL, ln 1alwan, LreaLed
lnlually as severe CA
Lmplrlc lC ln 43
Lmplrlc lC wlLh lower 100
day morLallLy (40 vs. 68,
p=0.02). C8 deaLh= 0.36,
p<0.01.
63 became culLure negauve
wlLh lC alone, no delay ln
sLarung 18 rx ln emplrlc lC
group
1seng ?1, eL al. CrlL Care
2012, 16: 8207


Comb|nanon keg|mens Must Account Ior Loca|
M|crob|o|ogy
111 pauenLs wlLh PA
no slngle beLa-lacLam
more Lhan 80
eecuve, addlng clpro
of llule lncremenLal
beneL
Amlkacln more acuve vs.
gram -negauves Lhan
qulnolones
8eardsley !8, eL al.
ChesL 2006, 130:
787-793.
AMINCGLCCSIDLS
8lnd Lo Lhe 30 S rlbosomal subunlL of bacLerla and
lnLerfere wlLh proLeln synLhesls
Cram - negauve specLrum , lncludlng . aeruglnosa
Synergy when comblned wlLh anu- seudomonal beLa-
lacLams
Amlkacln ls generally Lhe mosL acuve slnce lL ls less
suscepuble Lo enzymauc lnacuvauon. 1obramycln more
acuve Lhan genLamlcln.
oor resplraLory peneLrauon, lnacuve aL acld pP,
nephroLoxlc
Cnce dally doslng posslble

harmacodynam|cs of Am|nog|ycos|des
ConcenLrauon-dependenL bacLerlal kllllng, probably
besL glven once dally (? Less Loxlc, more eecuve)
eak/MlC and AuC/MlC (AulC) correlaLe wlLh
ouLcome, AulC LargeL for good resulL, ls > 123.
eak/MlC rauo should be 8 Lo 10-fold for a cllnlcal
response of > 90 and AulC aL leasL 123.
eak/MlC rauo of 8-10 and AulCs > 100 can also
reduce Lhe raLe of emergence of reslsLanL muLanLs
durlng Lherapy
AulCs of 230 are capable of kllllng bacLerlal
paLhogens on day 1 of Lherapy

Use of an Am|nog|ycos|de Improves VA Morta||ty
rospecuve observauonal
sLudy of 136 vA pauenLs
Lower morLallLy lf lnlual
Lherapy wlLh a beLa-lacLam/
8Ll and also a Lrend wlLh an
amlnoglycoslde.
8ecommend Lo conslder
uslng amlnoglycosldes ln
comblnauon as emplrlc
Lherapy, ln Sl1L Cl
CC8 AC LnL18A1lCn
lowler 8A, eL al. ChesL 2003,
123:833-844
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
BL/BLI AG FQ Ceph
HR of
Death
p=<0.01
=0.08
> 0.2

1|gecyc||ne: ? Ior Ac|netobacter
Approved for SSS1l (and lnLra-abdomlnal
lnfecuons)
Sull no comparauve daLa on severe, bacLeremlc
lnfecuons (only 'compllcaLed')
noL approved for nosocomlal pneumonla
Low serum concenLrauons: emplrlc Lherapy for
less severe lnfecuons, where M8SA and Cn8
(AclneLobacLer, buL nC1 seudomonas
aeruglnosa)
1|gecyc||ne Vs. Im|penem Ior nA]VA
943 pauenLs , randomlzed, double-bllnd , mulucenLer sLudy.
1lgecycllne 100 mg, Lhen 30 mg q12 h wlLh opuonal ceazldlme
lmlpenem 300-1000 mg q8 h wlLh opuonal vancomycln
1lgecycllne non-lnferlor for cllnlcal emcacy
1lgecycllne slgnlcanLly worse ln vA pauenLs ln Lhe CL populauon
Mean AuC 13 lower ln vA Lhan non-vA, AuC/MlC was 60 lower
!"#$%&'()"&%* (),-)$## vA: Cllnlcal response 37 1lgecycllne, 93 lmlpenem
lrlere A1, eL al. ulagnosuc Mlcroblol lnfecL uls 2010, 68: 140-31
Comb|nanon 1herapy for Ac|netobacter
VA
33 pauenLs wlLh
carbapenem-reslsLanL
AclneLobacLer
19 wlLh vA
31 goL ugecycllne as
comblnauon Lherapy
21 cllnlcal success wlLh
comblnauon Lherapy
Cuner 8, eL al. lnfecuon
2011, 39:313-318


o|ymyx|ns for Ac|netobacter VA
1wo agenLs have been used : olymyxln 8 and L (collsun)
lv and aerosollzed Lherapy of Mu8 gram-negauves
8lnds Lo gram-negauve ouLer cell membrane leadlng Lo permeablllLy
change and cell deaLh
8acLerlcldal ln concenLrauon-dependenL fashlon
olymyxln 8: 1 mg= 10,000 lu
Collsun 2.3-3 mg/kg per day ln 2-4 dlvlded doses
1 mg= 12,300u, 80 mg= 1 Mllllon u
8educe dose Lo 160 mg (2 Mu) q 12, 24 and 36 h wlLh renal
dysfuncuon
1oxlclLy: renal (A1n), neuroLoxlclLy (neuromuscular block, confuslon,
aLaxla, vlsual dlsLurbances, dlzzlness)
lalagas and kaslakou. Clln lnfecL uls 2003, 40 : 1333-41
1herapy of MkSA |nfecnon

A. ls more eecuve uslng an anu-SLaphylococcal
penlclllln Lhan uslng llnezolld
8. Can be accompllshed wlLh elLher vancomycln or
llnezolld
C. Can be accompllshed wlLh dapLomycln, regardless of
Lhe slLe of lnfecuon
u. Wlll llkely be eecuve lf Lhe Lrough serum
concenLrauon ls 10 mg/L for an organlsm wlLh
an MlC > 1 mg/L
L. Can be done by maxlmlzlng vancomycln dose, whlch
has no rlsk of nephroLoxlclLy

1herapy of MkSA |nfecnon
A. ls more eecuve uslng an anu-SLaphylococcal
penlclllln Lhan uslng llnezolld
8. Can be accompllshed wlLh elLher vancomycln or
llnezolld
C. Can be accompllshed wlLh dapLomycln, regardless of
Lhe slLe of lnfecuon
u. Wlll llkely be eecuve lf Lhe Lrough serum
concenLrauon ls 10 mg/L for an organlsm wlLh
an MlC > 1 mg/L
L. Can be done by maxlmlzlng vancomycln dose, whlch
has no rlsk of nephroLoxlclLy

Vancomyc|n kes|stance and Increased
Morta||ty |n MkSA nA
163 pauenLs wlLh M8SA PA, vA
or PCA
73 wlLh MlC of aL leasL 1.3
mcg/mL
C8 of deaLh of 3.7 for each
lncrease of 1mcg/mL ln vanc
MlC, C8=2.97 aer
propenslLy ad[usLmenL
79 vanco Lrough > 10, 43 aL
leasL 13 mcg/mL
Paque nZ eL al. ChesL 2010,
138:1336-62
Vancomyc|n Nephrotox|c|ty Increases
as 1rough Leve|s Are Increased
8eLrospecuve sLudy 0f 166
pauenLs: vancomycln for > 48
hours, no vasopressors or
conLrasL dye, basellne Cr < 2.0
mg/dL
21 wlLh nephroLoxlclLy:
lncrease ln Cr by 0.3 or by >
30 (whlchever greaLer)
ln muluvarlaLe model, only
Lrough level correlaLed wlLh
LoxlclLy.
Lodlse eL al. Clu 2009, 49:
307-14
Vancomyc|n 1rough Concentranons
red|ct Lmcacy and 1ox|c|ty
31 pauenLs wlLh M8SA
pneumonla
nephroLoxlclLy: lncrease Cr
by 0.3 mg/dl or 30 from
basellne
8elauonshlp of Lrough/MlC
wlLh success, and Lrough
levels wlLh LoxlclLy
Suzukl ? eL al. ChemoLherapy
2012, 38:308-12
Efficacy
Toxicity

A|ternanves to Vancomyc|n aga|nst MkSA
SLrepLogramlns (qulnuprlsun/dalfoprlsun)
Cxazolldlnones (llnezolld)
Clycopepudes (Lelcoplanln)
uapLomycln: nC1 for pneumonla
1elavancln: !usL approved for vA due Lo M8SA
and MSSA
Cearollne: 4
Lh
generauon cephalosporln acuve
vs. M8SA. Approved for CA (noL M8SA)

Daptomyc|n
Cood gram-posluve drug (lncludlng M8SA and v8L)
8acLerlcldal drug
Cycllc llpopepude
ulsrupLs cell membrane funcuon
8eslsLance uncommon, mechanlsm unknown
noL used for pneumonla due Lo low resplraLory
LracL concenLrauons and lnacuvauon by surfacLanL
use ln endocardlus, SS1l, bacLeremla
Adverse eecLs - reverslble myopaLhy
Vancomyc|n vs. L|nezo||d
Vancomyc|n. Clycopepude, dlsrupLs cell wall/pepudoglycan synLhesls
ros: low reslsLance raLes, years of experlence
Cons: slow lncrease ln MlCs (w/l sensluve" range), poor lung
peneLrauon (12 serum levels), slowly bacLerlcldal,
nephroLoxlclLy
May overcome poor peneLrauon by synergy wlLh rlfampln
L|nezo||d
ros: good lung peneLrauon, lv/oral avallable, hlgh bloavallablllLy
orally, no renal dose ad[usLmenL
Cons: LhrombocyLopenla, opuc neurlus, lacuc acldosls (prolonged
Lherapy), drug lnLeracuons (seroLonln syndrome)
leLz MW , eL al. Lur ! Med 8es 2010, 13:307-13
40
L|nezo||d Concentranons |n Serum and
LLI of Cr|nca||y I|| VA anents
16 crlucally lll vA pauenLs
sLudled aL sLeady sLaLe
All wlLh laLe onseL vA
12 wlLh organlsms: 3
M8SA, 1 MSSA, 8 LnLerlc
gram negauves
Serum and LLl concenLrauons
aer 2 days of Lherapy
8lood aL 10, 20 30 and 43 mln and
1,2,4,8,12 hours aer lnfuslon
8AL 1 and 12 hours aer lnfuslon
Slmllar levels ln serum and LLl
8ange of eak
peneLrauon: 34-188
8ange of 1rough
peneLrauon: 28-220
8oselll eL al. CrlL Care Med 2003,
33, 1329-1333.
L|nezo||d Vs. G|ycopepndes for MkSA N
Llnezolld vs. glycopepudes ln 6 Lrlals wlLh 639 pauenLs wlLh M8SA proven
Cllnlcal success wlLh documenLed M8SA wlLh C8=1.23. p=0.009 (from 0.09)
by addlng Wunderlnk 2012 daLa
1hamllklLkul v, 1ongsal S. ChesL 2012, 142: 269

Aeroso||zed Annb|oncs
1argeL dellvery Lo slLe of lnfecuon
lncrease concenLrauons ln Lracheobronchlal
secreuons compared Lo parenLeral use (esp.
amlnoglycosldes)
Avold exposure Lo sysLemlc anubloucs
8educe poLenual for anublouc reslsLance
8educe sysLemlc slde eecLs
now 1o Cpnm|ze Aeroso| De||very of
Annb|oncs |n Venn|ated anents
ulLrasonlc or vlbraung plaLe nebullzers preferred Lo [eL nebullzers. 8u1 ulLrasonlc
nebs may heaL Lhe anublouc.
vlbraung plaLes can synchronlze wlLh lnsplrauon and up Lo 60 of reservolr
dose deposlLs ln lung. arucle slze < 3 mlcrons
lace vlbraung plaLe ln lnsplraLory llmb before Lhe ? connecLor and L11 up
nebullzed dose= sysLemlc lv dose + exLrapulmonary deposluon (Lublng, explraLory
lLer)
LlmlL lnsplraLory ow Lurbulence
ConLrolled mode venulauon (nC1 asslsL, and may need sedauon), v1 of 7-9
ml/kg, consLanL lnsplraLory ow, Mv < 6L/mln, 8=12, l/L rauo of 1:1, end
lnsplr pause of 20 of Lhe duLy cycle
8emove PML lLer , add humldlcauon lf dellvery ume > 30 mln
8ouby !!, eL al. AnesLheslology 2012, 117:1364-1380
Ad[uncnve Aeroso||zed Am|kac|n As art of
Comb|nanon 1herapy of MDk Gram-Neganves?
rospecuve randomlzed, conLrolled Lrlal of Au!unC1lvL aerosollzed amlkacln
400 mg 8lu vs. Cu vs. placebo, all wlLh ad[uncuve sysLemlc anubloucs
49.1 wlLh . aeruglnosa or AclneLobacLer baumanll.
use of proprleLary ulmonary uose uellvery SysLem (nekLar)
up Lo day 7: anubloucs were added (escalaLed) ln 14, 38 and 38 of Lhe
pauenLs ln Lhe q12 h, q24h, and placebo groups , 1he remalnder ln each group
had anubloucs elLher sLopped or subLracLed (de-escalaLed).
N|ederman MS, et a|.
Intens|ve Care Med|c|ne 2012,
38: 263-271.


Lnd= Mean of 7 days

1nLkA kINCILLS AND DCSING ICk VA
ApproprlaLe: MaLchlng anublouc sensluvlues of Lhe organlsm Lo Lhe
anublouc used.
AdequaLe: lncludes approprlaLe LuS correcL dose, peneLrauon Lo slLe of
lnfecuon, correcL rouLe and comblnauon Lherapy (lf needed)
need proper anublouc doslng (normal renal funcuon)
Clprooxacln: 400 mg q8h, Levooxacln 730 mg qu
lmlpenem 1 gm q 8P or 300 mg q 6h,Meropenem 1 gm q 6-8 h
lperaclllln/1azobacLam 4.3 gm q 6h
Cefeplme 2 gm q 8-12h
Ceazldlme 2 gm q 8h
CenLamlcln or 1obramycln 7 mg/kg / day or Amlkacln 20 mg/kg/
day
Llnezolld 600 mg q 12 h
vancomycln 13 mg/kg q12h

Ann-seudomona| Annb|oncs
Amlnoglycosldes: genLamlcln, Lobramycln, amlkacln
Culnolones: clprooxacln, hlgh dose levooxacln
8eLa lacLams
Anu-pseudomonal penlcllllns
Cephalosporlns: ceazldlme, cefeplme,
lmlpenem, meropenem, dorlpenem
AzLreonam
8eLa-lacLam/beLa-lacLamase lnhlblLor comblnauons:
plperaclllln/LazobacLam, ucarclllln/clavulanaLe

Monotherapy of nosocom|a| pneumon|a |n
venn|ated panents can be done |n the
absence of h|gh|y res|stant pathogens w|th
a|| of the fo||ow|ng except
A. clprooxacln
8. lmlpenem
C. cefeplme
u. plperaclllln/LazobacLam
L. genLamlcln

Monotherapy of nosocom|a| pneumon|a |n
venn|ated panents can be done |n the
absence of h|gh|y res|stant pathogens w|th
a|| of the fo||ow|ng except
A. clprooxacln
8. lmlpenem
C. cefeplme
u. plperaclllln/LazobacLam
L. genLamlcln

Why LMIkIC Comb|nanon 1herapy |n
VA?
Comblnauon Lherapy does nC1
lmprove morLallLy overall
revenL Lhe emergence of reslsLance durlng Lherapy
8u1 comblnauon Lherapy could reduce morLallLy ll
lL lncreases Lhe chance of approprlaLe Lherapy
8roader specLrum coverage Lhan wlLh one drug alone
(gram negauve and gram-posluve)
Mlxed lnfecuon: cover gram-posluves and gram-
negauves
lL ls used ln seudomonal bacLeremla
auenL ls sepuc: More rapld bacLerlal kllllng

GLNLkAL ISSULS ICk AN1I8IC1IC USL IN
1nL CkI1ICALL ILL
Ceneral Conslderauons
know local mlcroblology
SlLe of lnfecuon
auenL rlsk facLors: recenL hosplLallzauon, prolonged
hosplLallzauon, recenL anublouc use, lmmune sLaLus,
orlgln (communlLy, nurslng home, hosplLal)
Lmphasls on proper doslng
Speclc anublouc lssues
Avold dual beLa-lacLam Lherapy
LlmlL use of Lhlrd generauon cephalosporlns
Conslder sequence of Lherapy: ? LlmlL qulnolones Lo
second eplsode of lCu lnfecuon

C1nLk kINCILLS CI AN1I8IC1IC USL IN
1nL CkI1ICALL ILL
LlmlLed need for comblnauon Lherapy
8acLeremla, neuLropenla, broad specLrum coverage
Conslder 3 day amlnoglycoslde Lherapy ln comblnauon wlLh a
beLa-lacLam when Lreaung . aeruglnosa
use an emplrlc Lherapy reglmen LhaL lncludes agenLs dlerenL
from whaL Lhe pauenL has recenLly recelved
8e-evaluaLe pauenL durlng Lherapy
ShorLen durauon of Lherapy
SLop Lherapy ln some
Conslder aerosollzed Lherapy as an ad[uncL Lo reduce Lhe
durauon of Lherapy
Conslder aerosollzed anubloucs as ad[uncuve Lherapy for vA
wlLh Mu8 paLhogens

Annb|onc res|stance |n the ICU
A. ls commonly due Lo Lhe presence of LS8L's among S.
aureus
8. Makes approprlaLe emplrlc Lherapy less llkely
C. MandaLes never uslng vancomycln for emplrlc
Lherapy of vA
u. Can be prevenLed by regular use of anublouc
roLauon
L. Can be ellmlnaLed by prohlblung Lhe use of
anubloucs such as Lhe Lhlrd generauon cephalosporlns

Annb|onc res|stance |n the ICU
A. ls commonly due Lo Lhe presence of LS8L's among S.
aureus
8. Makes approprlaLe emplrlc Lherapy less llkely
C. MandaLes never uslng vancomycln for emplrlc
Lherapy of vA
u. Can be prevenLed by regular use of anublouc
roLauon
L. Can be ellmlnaLed by prohlblung Lhe use of
anubloucs such as Lhe Lhlrd generauon cephalosporlns
Increas|ng|y Common MDk athogens
(not a|| caus|ng pneumon|a)
LSkAL aLhogens needlng beuer Lheraples Lhan
currenLly avallable
./ 0)%"#,- (v8L)
1/ ),*%,2 (M8SA)
34%(2#%44) spp. and ./ "'4# wlLh LS8L's and
carbapenemases (kC's)
!"#$%&'()"&%*
52%,6'-'$)2 )%*,7#$'2) wlLh mulu-drug reslsLance
.$&%*'()"&%* spp.
8oucher PW, eL al. Clu 2009, 48:1-12

Grayson ML, L||opou|os GM. Sem|n kesp|r Infect. 1990,S:204-214.
Mechan|sms of
Annm|crob|a| kes|stance
uecreased permeablllLy of mlcroblal cell wall
alLered porln channels
prlmary mechanlsm of gram-negauves Lo
!-lacLamases
Anublouc lnacuvauon
beLa-lacLamases, AC lnacuvaung enzymes, oLher
lnacuvaung enzymes
AlLerauon of anublouc LargeL slLe
8, unA gyrase, 8nA polymerase
Acuve eMux of Lhe anublouc

Mechan|sms of kes|stance: !"#$%&'&()" )(%
+,$- !$'."

AdapLed from Llvermore uM. 84#$ 9$0%"& :#2/ 2002,34:634-640.
!-|actams
Lnter 1hru
or|n Channe|s
Meropenem
|s pumped
out wh||e
|m|penem
|s not
Lmux System
Lx|t orta|
(CprM)
Cuter
Membrane
er|p|asm
L|nker
L|poprote|n
(Mex A)
Cytop|asm|c
Membrane
Lmux System ump (Mex 8)
or|n

k|sks for LS8L roduc|ng Crgan|sms and
Appropr|ate 1herapy
rospecuve observauonal sLudy of 433 eplsodes
of k. pneumonlae bacLeremla (233 nosocomlal)
ln 12 hosplLals
30.8 nosocomlal, 43.3 ln lCu wlLh LS8L's
8lsks for LS8L's: prevlous anublouc rx. (>2
days ln lasL 14 days) wlLh 8-lacLam conLalnlng
oxylmlno group (C8= 3.9). no rlsk wlLh
cefeplme, carbapenem, qulnolone,
amlnoglycoslde. CLher rlsks: 1n, renal
fallure, burns.

aLerson eL al: Ann lnLern Med 2004, 140:26-32.

Annb|onc 1herapy |n the resence of an
LS8L-produc|ng Crgan|sm
Carbapenem use assoclaLed wlLh
slgnlcanLly lower 14-day
morLallLy due Lo LS8L-produclng
3 ;$%,-'$#)% bacLeremla
Carbapenem monoLherapy
superlor Lo LhaL of qulnolone or
non-carbapenem -lacLams
use of a carbapenem <3 days
onseL of bacLeremla due Lo LS8L-
produclng organlsm assoclaLed
wlLh slgnlcanLly lower morLallLy
aterson DL et a|. /01( 2(3#45 61". 2004,39:31-37.
0
10
20
30
40
50
60
70
80
90
100
%

M
o
r
t
a
l
i
t
y

8LlC=-lacLam/-lacLamase lnhlblLor comblnauon
AMC=amlnoglycoslde
no Abx=no anubloucs

1he koot of 1he rob|em Is Us|ng 1oo Many
Annb|oncs. Is kestr|cnon the Answer??

Annm|crob|a| Stewardsh|p
Muludlsclpllnary approach: lu, pharmacy, mlcroblology, epldemllogy,
( CkI1ICAL CAkL: NC1 MLN1ICNLD)
2 CC8L S18A1LClLS
rospecuve audlL wlLh lnLervenuon and feedback ( A-l)
lormulary resLrlcuon and preauLhorlzauon Lo conLrol reslsLance (8-ll)
SupplemenLal sLraLegles
Lducauon
Culdellnes wlLh local mlcroblology (A-l)
Anumlcroblal cycllng (C-ll)
Anublouc order forms (8 ll), Comblnauon Lherapy (C-ll)
ue-escalauon (A-ll)
uose opumlzauon (A-ll)
lv Lo oral converslon (A-lll)
uelllL 1P, eL al. Clu 2007, 44: 139-77
Summary of key o|nts
urugs LhaL klll ln a concenLrauon dependenL fashlon need Lo have eak/MlC
rauo or AulC opumlzed: amlnoglycosldes, qulnolones. Cnce dally doslng.
urugs LhaL klll ln a ume dependenL fashlon need Lo have serum concenLrauon
above Lhe MlC of Lhe LargeL organlsm for aL leasL 40 of Lhe doslng lnLerval:
beLa-lacLams, cephalosporlns, carbapenems. rolonged or conunuous lnfuslon.
LlmlLauons of older agenLs: qulnolones vs. 5/ )%*,7#$'2), qulnolones for vA,
vancomycln vs. M8SA wlLh MlC > 1 mcg/ml
ulsungulsh approprlaLe from adequaLe Lherapy
8eneLs of comblnauon Lherapy: emplrlc rx of Mu8 paLhogens, bacLeremlc .
aeruglnosa, sepuc shock
LS8L producers: lnduced by Lhlrd gen cephs, besL rx ls carbapenem
Anumlcroblal sLewardshlp: de-escalauon, local proLocols for Lherapy, dose
opumlzauon, nC1 resLrlcLed access Lo anubloucs